rs1140047

Variant names:

• chr11-18306137-G-T
• rs1140047
• NM_181507.2:c.822C>A

Your query was ambiguous. Multiple possible variants found:

• chr11-18306137-G-T
• chr11-18306137-G-C

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_181507.2(HPS5):​c.822C>A​(p.Leu274Leu) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.714 in 1,597,472 control chromosomes in the GnomAD database, including 410,799 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L274L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.73 (40614 hom., cov: 32)
  • Exomes 𝑓: 0.71 (370185 hom.)
• Consequence: HPS5 NM_181507.2 splice_region, synonymous
• Scores: Splicing: ADA: 0.00007983
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.30
• Publications: 25 publications found

Genes affected

HPS5 (HGNC:17022): (HPS5 biogenesis of lysosomal organelles complex 2 subunit 2) This gene encodes a protein that may play a role in organelle biogenesis associated with melanosomes, platelet dense granules, and lysosomes. This protein interacts with Hermansky-Pudlak syndrome 6 protein and may interact with the cytoplasmic domain of integrin, alpha-3. Mutations in this gene are associated with Hermansky-Pudlak syndrome type 5. Multiple transcript variants encoding two distinct isoforms have been identified for this gene. [provided by RefSeq, Jul 2008]

HPS5 Gene-Disease associations (from GenCC):

• Hermansky-Pudlak syndrome 5

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae)
• Hermansky-Pudlak syndrome without pulmonary fibrosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 11-18306137-G-T is Benign according to our data. Variant chr11-18306137-G-T is described in ClinVar as Benign. ClinVar VariationId is 163678.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.3 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.946 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_181507.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HPS5	NM_181507.2	MANE Select	c.822C>A	p.Leu274Leu	splice_region synonymous	Exon 7 of 23	NP_852608.1	Q9UPZ3-1
	HPS5	NM_001440902.1		c.822C>A	p.Leu274Leu	splice_region synonymous	Exon 7 of 24	NP_001427831.1
	HPS5	NM_001440903.1		c.822C>A	p.Leu274Leu	splice_region synonymous	Exon 7 of 24	NP_001427832.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HPS5	ENST00000349215.8	TSL:1 MANE Select	c.822C>A	p.Leu274Leu	splice_region synonymous	Exon 7 of 23	ENSP00000265967.5	Q9UPZ3-1
	HPS5	ENST00000396253.7	TSL:1	c.480C>A	p.Leu160Leu	splice_region synonymous	Exon 6 of 22	ENSP00000379552.3	Q9UPZ3-2
	HPS5	ENST00000438420.6	TSL:1	c.480C>A	p.Leu160Leu	splice_region synonymous	Exon 6 of 22	ENSP00000399590.2	Q9UPZ3-2

Frequencies

GnomAD3 genomes AF: 0.727 AC: 110426 AN: 151934 Hom.: 40566 Cov.: 32

Gnomad AFR AF: 0.764

Gnomad AMI AF: 0.763

Gnomad AMR AF: 0.746

Gnomad ASJ AF: 0.590

Gnomad EAS AF: 0.969

Gnomad SAS AF: 0.750

Gnomad FIN AF: 0.720

Gnomad MID AF: 0.601

Gnomad NFE AF: 0.689

Gnomad OTH AF: 0.711

GnomAD2 exomes AF: 0.732 AC: 183949 AN: 251348 AF XY: 0.723

Gnomad AFR exome AF: 0.765

Gnomad AMR exome AF: 0.812

Gnomad ASJ exome AF: 0.580

Gnomad EAS exome AF: 0.976

Gnomad FIN exome AF: 0.715

Gnomad NFE exome AF: 0.684

Gnomad OTH exome AF: 0.682

GnomAD4 exome AF: 0.713 AC: 1030552 AN: 1445420 Hom.: 370185 Cov.: 29 AF XY: 0.711 AC XY: 511979 AN XY: 720278

African (AFR) AF: 0.760 AC: 25205 AN: 33150

American (AMR) AF: 0.803 AC: 35889 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.581 AC: 15114 AN: 26030

East Asian (EAS) AF: 0.962 AC: 38134 AN: 39620

South Asian (SAS) AF: 0.721 AC: 61938 AN: 85926

European-Finnish (FIN) AF: 0.713 AC: 38095 AN: 53412

Middle Eastern (MID) AF: 0.544 AC: 3122 AN: 5744

European-Non Finnish (NFE) AF: 0.702 AC: 770448 AN: 1097030

Other (OTH) AF: 0.712 AC: 42607 AN: 59804

GnomAD4 genome AF: 0.727 AC: 110530 AN: 152052 Hom.: 40614 Cov.: 32 AF XY: 0.730 AC XY: 54286 AN XY: 74334

African (AFR) AF: 0.764 AC: 31696 AN: 41492

American (AMR) AF: 0.746 AC: 11394 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.590 AC: 2047 AN: 3470

East Asian (EAS) AF: 0.969 AC: 5019 AN: 5182

South Asian (SAS) AF: 0.750 AC: 3607 AN: 4808

European-Finnish (FIN) AF: 0.720 AC: 7598 AN: 10548

Middle Eastern (MID) AF: 0.588 AC: 173 AN: 294

European-Non Finnish (NFE) AF: 0.689 AC: 46797 AN: 67966

Other (OTH) AF: 0.714 AC: 1508 AN: 2112

Alfa AF: 0.698 Hom.: 127952

Bravo AF: 0.733

Asia WGS AF: 0.888 AC: 3084 AN: 3478

EpiCase AF: 0.675

EpiControl AF: 0.671

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	2	Hermansky-Pudlak syndrome 5 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	7.0
DANN	Benign	0.71
PhyloP100		1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=92/8	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000080
dbscSNV1_RF	Benign	0.022
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1140047; hg19: chr11-18327684;